The nervous system is divided broadly into two categories: the peripheral nervous system and the central nervous system. The peripheral nervous system is composed of sensory neurons and the neurons that connect them to the spinal cord and brain, which make up the central nervous system, and performs nerve conduction.
The peripheral nervous system is divided into the somatic nervous system and the autonomic nervous system, and the somatic nervous system is divided into cranial nerves and spinal nerves. Meanwhile, depending on the function thereof, the somatic nervous system is divided into afferent (or sensory) nerve fibers and efferent (or motor) nerve fibers. The afferent (or sensory) nerve fibers are responsible for transmitting nerve signals derived from sensory receptors to central nerves, and the efferent (or motor) nerve fibers are responsible for performing nerve conduction from the brain and spinal cord to muscles and secretory glands.
Cranial nerves, peripheral nerves emerging from the brain, are organized into twelve pairs which consist of sensory, motor and mixed nerve fibers. The twelve pairs of cranial nerves are olfactory nerves, optic nerves, oculomotor nerves, trochlear nerves, trigeminal nerves, abducens nerves, facial nerves, vestibulocochlear nerves, glossopharyngeal nerves, vagus nerves, accessory nerves and hypoglossal nerves.
Of these, nerves composed of sensory or combined nerve fibers are olfactory nerves, optic nerves, abducens nerves, facial nerves, vestibulocochlear nerves, glossopharyngeal nerves and vagus nerves.
The spinal nerves, peripheral nerves coming out of the spinal cord, are organized into 31 pairs in the left and right sides of the body: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The spinal nerves are all mixed nerve fibers, each of which contains both sensory nerve fibers supplied to the skin, and motor nerves supplied to the muscles.
Sensory nerve fibers, i.e., sensory nerves, accurately serve to transmit stimuli, e.g., light, sound, temperature or touch received by sensory acceptors such as the visual organ, auditory organ, olfactory organ, gustatory organ and the skin, to the central nervous system. Then, the nerve signals are finally transmitted from the central nervous system to the sensory areas, e.g., visual and auditory areas, in the cerebral cortex, to perform normal sensation.
However, these peripheral nerves may be injured by factors such as viral infection, tumors, cancers, ischemia, trauma, compression, pharmacotherapy or actinotherapy. The injury symptoms include peripheral tingling, numbness and burning sensation, decrease in intrinsic and vibration angles of joints, and joint pain, dysesthesia, chills and burning, etc.
These peripheral nerve injuries are generally divided into traumatic peripheral nerve injuries, congenital peripheral nerve injuries, inflammatory peripheral nerve injuries, toxic peripheral nerve injuries, and other tumorous or idiopathic peripheral nerve injuries (Dyck, et al. WB Sounders Co. Philadelphia. Peripheral Neuropathy, 1435-1451, (1984); Brown W F. The place of Electro-myography in the analysis of Traumatic peripheral nerve lesion. In (1987): Brown W F, Bolton, C F. Clinical Electromyography. Butterworth, 159-175).
Of these, the traumatic peripheral nerve injuries increasingly occur in more various patterns, due to increased industrial mishaps and traffic accidents, and generalized sport and leisure which are caused by the industrial development and rapid automobile popularization.
In the treatment of traumatic peripheral nerve injury caused by physical injury to nerves, symptomatic therapy is currently used for the purpose of symptom relief. For example, there are operations, e.g., removal of the wound site around the injured tissue to promote regeneration of peripheral nerves (Kline D G et al. Civilian gunshot wound to brachial plexus. 70, 166-174, (1989)), an operation to directly bind upper and lower portions of the injured site (Kline D G, Judice D J: Operative management of selected brachial plexus lesions. J Neurosurg 58, 631-649, (1983)), and peripheral nerve grafting (Millesi H; Brachial plexus injuries. Nerve grafting. Clin Orthop 237, 36-42. (1988)).
Meanwhile, there are several conservative therapies, e.g., electrotherapy to prevent the degeneration of neuromuscular junctions and muscular atrophy, while awaiting voluntary nerve regeneration (al-Amood W S, Lewis D M, Schmalbruch H, Effects of chronic electrical stimulation on contractile properties of long-term denervated rat skeletal muscle. J Physiol (London) 441, 243-256, (1991), and exercise therapy generally-used in partial injuries, to prevent weakness and atrophy of muscular strength and promote collateral sprouting of nerves. Another conservative therapy is the use of an orthotic to protect the joint and prevent muscle and ligament injury (Gravois M, Garrison S J, Hart K A, Lehmkuhl L D: Physical Medicine and Rehabilitation, Massachusetts: Blackwell Science, 432-433, (2000)). Furthermore, there is a drug therapy to relieve the pain caused by nerve injury using local anesthetics and antispasmodics.
However, the operative therapies may induce secondary injury, and clinically useful drugs which directly act on the injured peripheral nerve system to fundamentally treat the injury are hardly known in the field of drug therapy.
Meanwhile, the granulocyte-colony stimulating factor (G-CSF) specifically acts on neutrophil stem cells to promote the proliferation and differentiation of neutrophils and increase antibody-dependent cell-mediated cytotoxicity. In addition, G-CSF promotes IgA-mediated phagocytosis and increases superoxide production performance. Accordingly, G-CSF is known to improve reactivity to chemotactic peptides, inhibits occurrence of infectious diseases, and reduces the frequency of pyrexia.
In addition, G-CSF is believed to have little effect upon leukemic stem cells in the body, since it acts on more differentiated bone marrow cells, as compared to other CSFs such as granulocyte-macrophage CSFs (GM-CSFs). Accordingly, G-CSF is widely used for anti-cancer chemotherapy, administration of a great amount of anti-cancer agent, combination therapy with radiotherapy, and a drug for promoting rehabilitation of neutrophils after bone narrow implantation (Julie M. Vores et al., Clinical Applications of Hematopoietic Growth Factors, Journal of Clinical Oncology, 13, 1023-1035, (1995)).
Such G-CSF acts as a hematopoietic agent that primarily acts on the proliferation and differentiation of neutrophils, which is primarily used for the treatment of neutropenia caused by bone marrow transplantation and anti-cancer administration and is responsible for increasing neutrophils in myelodysplastic syndromes, aplastic anemia, serious chronic neutropenia (such as congenital, cyclic or idiopathic neutropenia), HIV-infected patients and preventing infectious diseases caused by decreased neutrophils.
In recent years, a great deal of research has been conducted on, in addition to clinical use of G-CSF for the neutropenia, on administration of G-CSF alone or in combination with an antibiotic for the treatment of infectious diseases, based on the expectation that G-CSF promotes neutrophil production and reinforces neutrophil performance, thus being potent for preventing and treating various infectious diseases such as pneumonia or septicemia.
Several therapeutic agents using G-CSF, based on various physiological activities, were suggested. For example, Korean Patent Application No. 10-2005-7019543 discloses a diabetes treatment comprising one or more stem cell-recruiting factors such as G-CSFs as active ingredients. In addition, Korean Patent Application No. 10-2006-7008042 discloses a fibroblast-mobilizing agent using G-CSF to simply recruit fibroblasts into wounded tissues and engraft the fibroblasts in the wounded tissues, thereby healing the wounds.
However, there is no research that recognizes the treatment of traumatic peripheral nerve injuries as a novel use of G-CSF.